Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan.
Department of Cardiology, Sendai Medical Association Hospital, Satsumasendai, Kagoshima, Japan.
J Clin Lipidol. 2019 Mar-Apr;13(2):335-339. doi: 10.1016/j.jacl.2019.01.004. Epub 2019 Jan 16.
More than 2500 variants of the low-density lipoprotein receptor (LDLR) gene have been reported in familial hypercholesterolemia (FH). However, the effects of these variants on the pathophysiology of FH have not been fully clarified.
Our aim was to examine whether the c.2579C>T (p.A860V) variant of the LDLR gene affects the phenotype of FH. We present 2 index cases harboring biallelic LDLR variants, including the c.2579C>T (p.A860V) variant, which is defined as having uncertain significance in ClinVar.
Genetic analysis was performed for coding regions of the LDLR and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes in 2 families. Detailed clinical and biochemical data were gathered from family members.
In one family, the index case involved a patient who harbored biallelic A860V and c.1528-1529insA (p.T510Nfs) LDLR variants and had 8 children; the affected children had the p.T510Nfs variant, and the unaffected children had the A860V variant. In another family, the patient involved in the index case and his sister had biallelic A860V and c.1845+2T>C LDLR variants. There was no difference in FH phenotype between these siblings and their relatives who were heterozygous for the c.1845+2T>C variant. In addition, the allele frequency of the A860V variant (0.0062/0.0095) in the Japanese population, as indicated by 2 databases, was higher than expected based on the prevalence of heterozygous FH in the Japanese population (0.002-0.005).
This is the first report to show using pedigree-based genetic analysis that the A860V variant of the LDLR gene is a benign variant.
家族性高胆固醇血症（FH）中已报道超过 2500 种低密度脂蛋白受体（LDLR）基因突变。然而，这些突变对 FH 病理生理学的影响尚未完全阐明。
我们旨在研究 LDLR 基因 c.2579C>T（p.A860V）突变是否影响 FH 的表型。我们报告了 2 个索引病例，均携带 LDLR 基因的双等位基因突变，包括定义为 ClinVar 中意义不确定的 c.2579C>T（p.A860V）突变。
对 2 个家系的 LDLR 和前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）基因的编码区进行了基因分析。从家系成员中收集了详细的临床和生化数据。
在一个家系中，索引病例涉及一位患者，其携带双等位基因 A860V 和 c.1528-1529insA（p.T510Nfs）LDLR 突变，有 8 个孩子；受影响的孩子携带 p.T510Nfs 突变，未受影响的孩子携带 A860V 突变。在另一个家系中，索引病例患者及其妹妹均携带双等位基因 A860V 和 c.1845+2T>C LDLR 突变。这些兄弟姐妹与其携带 c.1845+2T>C 变体的杂合亲属的 FH 表型无差异。此外，2 个数据库显示，日本人群中 A860V 突变的等位基因频率（0.0062/0.0095）高于日本人群中杂合 FH 的患病率（0.002-0.005）。
这是首例通过基于家系的遗传分析表明 LDLR 基因的 A860V 突变是良性突变的报告。
